This invention is in the field of optical measurement techniques, and relates to a method and deuce for measuring the concentration of glucose or other substances in blood, such as cholesterol albumin, etc. The present invention is useful for both in vitro and in vivo measurements.
Optical methods for determining the chemical composition of blood are known and are typically based on spectrophotometric measurements enabling the indication of the presence of various blood constituents based on known spectral behaviors of these constituents. These spectrophotometric measurements can be effected either In vitro or in vivo. The measurements in vitro are invasive, i.e., require a blood sample to be physically withdrawn and examined. At present, these measurement have become unpopular, due to the creasing danger of infection.
The only accepted non-invasive optical measurement technique for measuring blood parameters is pulse oximetry. However, pulse oximetry provides solely for the determination of oxygen saturation in blood. For other blood parameters, the determination is too problematic, because their absorption spectral behavior in red-NIR regions is not as reliable as for oxygenized and non-oxygenized hemoglobin. As a result, patients suffering from diabetes who need to control their disease by monitoring their blood glucose levels, especially after walking, eating or exercising, still have to draw a small blood sample from their fingertip, apply and use monitoring strips and use a small machine.
Various techniques have been developed aimed at facilitating the measurement of the concentration of glucose in a patient""s blood. These techniques are disclosed, for example, in the following publications:
xe2x80x9cBlood Analysis: Noninvasive Methods Hover on Horizonxe2x80x9d, K. Robinson, Biophotonics International, May/June 1998;
xe2x80x9cGlucose- and Blood-Monitoring Systems Vie for Top Spotxe2x80x9d, Susan M. Reiss, Biophotonics International, May/June 1997;
xe2x80x9cOptical Glucose Sensing in Biological fluids: and Overiewxe2x80x9d, Roger J. McNichols, Gerard Cote, Journal of Biomedical Optics, January 2000, Vol. 5. No. 1, pp. 5-16; and
U.S. Pat. Nos. 5,209,231; 5,398,681; 5,448,992; 5,687,721; 5,692,504; 5,551,422; 5,676,143; 5,533,509; 5,687,721; 4,901,728.
Most of the above techniques are based on the known phenomenon consisting in that glucose, being an optically active medium, rotates polarized light, and the higher the concentration of glucose, the greater the rotation.
According to all prior art techniques, measurements are applied to a blood flow containing medium during the state of normal blood flow, and the measured signals are pulsatile-related signals.
A different technique for measuring various blood-related parameters has been developed and disclosed in WO 99/65384, assigned to the assignee of the present application. This technique utilizes the so-called occlusion-release mode, wherein over-systolic pressure is applied to a patient""s blood perfused fleshy medium so as to create the state of blood flow cessation at a measurement location. Optical measurements are applied during a time period including cessation time, during which the state of blood flow cessation is maintained, and time dependencies of xe2x80x9cnon-pulsatilexe2x80x9d light responses of the medium are determined for at least two wavelengths of incident radiation. This technique enables to significantly enhance the light response signal, as compared to that obtained with the pulse oximetry.
The main idea of the present invention is based on measuring the time variations of light responses of a blood containing medium corresponding to different polarization states of detected light. Generally speaking, the present invention is based on establishing the correlation between the kinetics of changes in the properties of blood containing scattering affecting or optically active substances (mainly, glucose), and the kinetics of changes in the state of polarization of linearly polarized radiation scattered by tissue containing blood vessels and capillaries.
Thus, according to one aspect of the present invention, there is provided a method of optical measurements for determining the concentration of a substance in a patient""s blood, the method comprising the steps of
performing optical measurement sessions within a certain period of time by illuminating a measurement location in a blood containing medium with incident light of at least one selected wavelength, detecting, at each measurement session, at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generating data representative thereof and
obtaining measured data in the form of at least two time variations of the light responses of the medium, a relation between the time variations being indicative of the concentration of the substance in blood
It should be understood that the term xe2x80x9cmeasurement sessionxe2x80x9d signifies at least two measurements, taken either sequentially or simultaneously, including the illumination of the measurement location with at least one wavelength of incident light and the detection of at least two light responses characterized by different polarization states of the detected light, respectively. By performing more than one measurement session, either continuously or timely separated, the time variations of light responses of different polarization states are obtained.
Preferably, the present invention utilizes the principles of the above-indicated occlusion-release technique to apply optical measurements during the state of blood flow cessation at a measurement location. Accord to the present invention, however, measurements are carried out in a manner to detect at least two light responses of the medium characterized by two different states of polarization, respectively, and to measure time variations of the light responses. To this end, pressure is applied to a location on the blood containing medium (e.g, over-systolic pressure applied to the patient""s blood perfused fleshy medium, in the case of non-invasive measurements), and the measurement location to which the optical measurement sessions are applied, is located downstream of the pressed location with respect to the blood flow direction. The application of pressure causes artificial change in the velocity of blood, namely, causes the state of blood flow cessation at a location downstream of the pressurized location. The artificial change in the blood results in the aggregation of red blood cells (Rouleaux effect) with time-varying shape and size of aggregates. At the state of the blood flow cessation, when there is actually no blood flow, no shear forces prevent the erythrocytes"" aggregation process. Hence, the light response (transmission or reflection) of the blood perfused fleshy medium at the state of the blood flow cessation can be considered as the time dependence of scattering in a system growing scatterers.
Glucose, being the main optically active substance in blood, influences the optical characteristics of scattered and partly absorbed radiation in a complicated manner. More specifically, glucose introduces changes in the ratio of refraction indices of erythrocytes and surrounding plasma, and introduces spectrally dependent optical rotation (rotary dispersion). These-factors lead to dynamic changes in the state of polarization, in particular the polarization or depolarization degree, under the condition of kinetic changes in the aggregates in the case of periodical application of occlusion (occlusion-release sessions).
Dynamic multiple scattering increases the optical path of radiation scattered from a blood sample and, consequently, the angle of rotation of polarization of incident light. Additionally, it is known that the state of polarization of incident light affects the light scattering properties (via the Stokes parameters). Thus, the results of the transmission or reflection measurement will be governed by the state of polarization of the incident light. This means that any change in the relative refraction index of the scatterer (i.e., red blood cell in the case of blood) will affect the measured light intensity differently depending on the state of polarization of the incident light. Since the concentration of the scattering affecting substance in blood (e.g., an optically active substance such as glucose) affects the relative refractive index, any parameter utilizing the combination of two or more different polarization measurements will be sensitive to the concentration of this substance.
Thus, the optically active or scattering affecting substance in a medium (e.g., glucose in blood) may influence the optical characteristics of the medium in two different ways: (1) through the optical activity and (2) through the polarization dependent scattering. The optical response of the system in the polarization dependent measurement set-up provides additional information relating to the substance concentration in the medium.
In order to pick up substantially multiple-scattered radiation, an analyzer means of a radiation receiving unit is mounted such that its plane of preferred potion is oriented at a predefined angle (for example, orthogonal) to that of a polarizer means of a radiation source.
Generally, the measurements may be carried out with one wavelength of incident radiation lying in visual or near infrared spectra, but with two or more different polarization states of either the incident or the collected radiation. However, to increase the accuracy of measurement, taking into account the dispersion of optical rotation, the measurements with different polarization states of the light response may be repeated for two or more different wavelengths of incident radiation. To decrease incidental fluctuations, multiple measurement sessions are performed by the alternation of aggregation-deaggregation cycles (i.e., multiple occlusion-release sessions) with the synchronization of start and end points of measurements and with subsequent statistical averaging
By standardizing the measurement conditions and performing preliminary calibration on blood samples with known concentrations of glucose, the method of the present invention enables to determine the level of glucose in blood in-vitro, as well as in-vivo.
Thus, the method consists of determining quantitative relationship between the kinetics of changes in polarized light (while at the xe2x80x9cflow-stopxe2x80x9d mode) passed through an absorbing and scattering medium that contains a certain concentration of scattering affecting substance, and the concentration of this substance. The medium under measurements is the patient""s blood perfused fleshy medium, e.g., his finger, when dealing with in vivo measurements, or a suspension of RBC in cuvette, in the case of in vitro measurements.
The method consists of two stages: At the first stage, correlation between the concentration of a substance (glucose) and a predefined, non-dimensional parameter, R, is measured. This measurable parameter R is indicative of some kind of a mathematical relation between the two opto-kinetic signals (occlusion curves), generated by scattering, absorption and polarization changes, occurring during the state of blood aggregation.
For example, the parameter R may present a parametric slope (tangent of the angle of inclination) of a curve representative of multiple scattered polarized light. Graphically, this is an inclined line in coordinates (T1xe2x88x92T2), or (logT1xe2x88x92logT2), wherein T1 is the light response of the medium with one state of polarization (e.g., linearly polarized light), and T1 is the light response of the medium with another state of polarization. These different light responses may, for example, be obtained by illuminating the medium with incident light of the same wavelength but different polarization states. Since this curve is indicative of the kinetic curves reflecting the complete attenuation of the polarized and unpolarized light, respectively, it actually presents a curve of the multiple scattered polarized light.
Another possible example of such a parameter R may be the degree of depolarization of the collected light, which is the function of time and can be calculated as follows: (t1xe2x88x92T2)/(T1+T2). This function is different for different wavelengths of incident light.
The measurable parameter R (e.g., parametric slope of the curve T1(T2) or degree of depolarization) is indicative of the glucose concentration in the blood under measurements. To determine the glucose concentration Cgl, reference data in the form of a calibration curve R(Cgl) is previously obtained. The calibration curve may be different for different measurement devices. Thus, at the second stage, the concentration of glucose is determined using the calibration curve.
The calibration curve may be obtained by applying the measurements of the present invention to blood samples (or plurality of patients) with the known concentration of glucose. The calibration curve may be plotted with respect to the same patient, by causing changes in the concentration of glucose in his blood and applying the technique of the present invention for determining the corresponding value of the parameter R.
Thus, according to another aspect of the present invention, there is provided a method of optical measurements for determining the concentration of a substance in a patient""s blood, the method comprising the steps of:
creating a state of blood flow cessation within a measurement location in a blood flow containing medium, and maintaining said state during a certain cessation time;
performing optical measurement sessions within a time period including said certain cessation time, the optical measurements including illumination of the measurement location with incident light of at least one selected wavelength, detection, at each measurement session, of at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generation of data representative thereof;
obtaining measured data in the form of at least two time variations of the light responses of the medium, a relation between the time variations being indicative of the concentration of the substance in blood.
According to yet another aspect of the present invention, there is provided a method of optical measurements for non-invasively determining the concentration of a substance in a patient""s blood, the method comprising the steps of:
applying over-systolic pressure to a location on the patient""s blood perfused fleshy medium, thereby creating a state of blood flow cessation within a measurement location downstream of the location of application of pressure, and maintaining said state during a certain cessation time;
performing optical measurement sessions within a time period including said certain cessation time, the optical measurements including illumination of the measurement location with incident light of at least one selected wavelength, detection at each measurement session, of at least two light response of the medium characterized by at least two different polarization states of detected light, respectively and generation of data representative thereof;
obtaining measured data in the form of at least two time variations of the light responses of the medium, a relation between the time variations being indicative of the concentration of the substrate in blood.
According to yet another aspect of the present invention, there is provided a method for determining the concentration of a substance in a patient""s blood, the method comprising the steps of:
providing reference data indicative of a preset measurable parameter as a function of values of said concentration;
creating a state of blood flow cessation within a measurement location in a cessation time;
performing optical measurement sessions within a time period including said certain cessation time, the optical measurements including illumination of the measurement location with incident radiation of at least one selected wavelength, detection, at each measurement session, of at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generation of measured data representative thereof;
utilizing the measured data for obtaining measurement results in the form of at least two kinetic curves of the light responses of the medium as functions of time corresponding to the different polarization states of the detected light;
analyzing said at least two kinetic curves for calculating said certain parameter indicative of relation between them, and
utilizing the calculated value and said reference data for determining the concentration of the substance in the patient""s blood.
According to yet another aspect of the present invention, there is provided a method for non-invasively determining the concentration of a substance in a patient""s blood, the method comprising the steps of:
providing reference data indicative of a preset measurable parameter as a function of values of said concentration;
applying over-systolic pressure to a location of the patient""s blood perfused fleshy medium, thereby creating a state of blood flow cessation within a measurement location downstream of the location of application of pressure with respect to the blood flow direction, and maintaining said state of the blood flow cessation during a certain cessation time being insufficient for irreversible changes in the fleshy medium;
performing optical measurement sessions within a period including said certain cessation time, the optical measurements including illumination of the measurement location with incident light of at least one selected wavelength detection, at each measurement session, of at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generation of data representative thereof;
utilizing the measured data for obtaining measurement results in the form of at least two kinetic curves of the light responses of the medium as functions of time corresponding to the different polarization states of the detected light;
analyzing said at least two kinetic curves for calculating said certain parameter indicative of relation between them, and
utilizing the calculated value and said reference data for determining the concentration of the substance in the patient""s blood.
To detect light beams with different polarization states, one of the following implementations is possible:
(1) The medium (at the measurement location) is illuminated with two beams of incident radiation having different polarization states (e.g., polarized and unpolarized light), and a specific polarization filtering, common for both beams of the incident light, is applied at the detection side.
To this end, the illumination unit may comprise two light sources (e.g., sequentially operable) generating two light beams, respectively, and comprises either a single polarizer mounted stationary in the optical path of one of the generated beams, or two polarizers with different orientations of their planes of preferred polarization mounted in the optical paths of the two beams, respectively. Alternatively, a single light source can be utilized to generate two timely separated beams of incident light. In this case, a polarizer of the illumination unit is shiftable between its operative and inoperative positions, being in and out of the optical path of the incident beam, respectively.
As for the detection means, it comprises a detector unit equipped with an analyzer mounted stationary in the optical path of light returned from the medium (e.g., transmitted), provided the plane of preferred polarization of the analyzer is specifically oriented with respect to that of the polarizer(s) of the illumination unit.
(2) The medium is illuminated with an incident beam having a predefined polarization state, and different polarization filtering is applied at the detection side with respect to two spatially separated light components of a transmitted (or reflected) beam, respectively. For this purpose, the illumination unit comprises a single light source emitting a beam of light, and a single polarizer mounted in the optical path of the emitted beam. The detection means comprises a pair of detector units and either two differently oriented analyzers mounted in front of the detector units, respectively, or a single analyzer mounted in front of one of the detector units only.
According to yet another broad aspect of the present invention, there is provided a measurement system for determining the concentration of a substance in a patient""s blood, the system comprising:
a measurement device that comprises a pressurizing assembly for applying pressure to a blood flow containing medium, so as to create a state of blood flow cessation at a measurement location in the medium downstream of the pressurized location with respect to the direction of blood flow, and a measuring unit for performing optical measurement sessions at said measurement location, the measuring unit comprising an illumination system and a light collection/detection system which are operable to detect, at each measurement session, at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generate measured data representative thereof; and
a control unit connectable to the measurement device for selectively operating said measuring unit and said pressuring assembly, such that the state of blood flow cessation is maintained during a certain cessation time and the optical measurement sessions are performed within a time period including said cessation time,
the control unit being responsive to said measured data to determine time variations of said at least two light responses of the medium corresponding to at least two different polarization states of the detected light, and analyze the time variations for determining a preset parameter measured as a relation between the time variations, and determining the concentration of said substance using reference data indicative of the preset measurable parameter as a function of values of the substance concentration.
According to yet another aspect of the present invention, there is provided a measurement system for non-invasively determining the concentration of a substance in a patient""s blood, the system comprising:
a measurement device that comprises a pressurizing assembly operable to apply over-systolic pressure to a location on the patient""s blood perfused fleshy medium, so as to create a state of blood flow cessation at a measurement location in the medium located downstream of the location of the application of pressure; and comprises a measuring unit operable to perform optical measurement sessions to said measurement location, the measuring unit comprising an illumination system and a light collection/detection system which are operable so as to detect at least two light responses of the medium characterized by at least two different polarization states of detected light respectively, and generate measured data representative thereof; and
a control unit connectable to the measurement device for selective operating said measuring unit and said pressurizing assembly, such that the state of blood flow cessation is maintained during a certain cessation time being insufficient for irreversible changes in the fleshy medium, and the optical measurement sessions are performed within a time period including said cessation time, the control unit being responsive to said measured data to determine time variations of said at least two light responses of the medium corresponding to at least two different polarization states of the detected light, and analyze the time variations for determining a preset parameter measured as a relation between the time variations, and determining the concentration of said substance using reference data indicative of the preset measurable parameter as a function of values of the substance concentration.
According to yet another aspect of the present invention, there is provided a measurement device for performing non-invasive optical measurement for determining the concentration of a substance in a patient""s blood, the device comprising
a pressurizing assembly operable to apply over-systolic pressure to a location on the patient""s blood perfused fleshy medium, so as to create a state of blood flow cessation at a measurement location in the medium located downstream of the location of application of pressure, and to maintain said state during a certain cessation time being insufficient for irreversible changes in the fleshy medium; and
a measuring unit operable to perform optical measurement sessions at said measurement location within a time period including said cessation time, the measuring unit comprising an illumination system and a light collection/detection system which are operable to detect, at each measurement session, at least two light responses of the medium characterized by at least two different polarization states of detected light, respectively, and generate measured data representative thereof, the measured data being indicative of time variations of said at least two light responses of the medium corresponding to at least two different polarization states of the detected light, a relation between said time variations being indicative of the concentration of said substance.